rs1114167316

Positions:

• chr3-4735314-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001378452.1(ITPR1):​c.5504T>C​(p.Leu1835Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.61

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ: 5.5951 (greater than the threshold 3.09). Trascript score misZ: 6.2026 (greater than threshold 3.09). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. GenCC has associacion of the gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 3-4735314-T-C is Pathogenic according to our data. Variant chr3-4735314-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 253023.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5504T>C	p.Leu1835Pro	missense_variant	44/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5459T>C	p.Leu1820Pro	missense_variant	43/61		NP_001161744.1
ITPR1	NM_001099952.4	c.5360T>C	p.Leu1787Pro	missense_variant	41/59		NP_001093422.2
ITPR1	NM_002222.7	c.5315T>C	p.Leu1772Pro	missense_variant	40/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5504T>C	p.Leu1835Pro	missense_variant	44/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5480T>C	p.Leu1827Pro	missense_variant	44/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5477T>C	p.Leu1826Pro	missense_variant	44/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5462T>C	p.Leu1821Pro	missense_variant	43/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5459T>C	p.Leu1820Pro	missense_variant	43/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5432T>C	p.Leu1811Pro	missense_variant	41/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5360T>C	p.Leu1787Pro	missense_variant	41/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5315T>C	p.Leu1772Pro	missense_variant	40/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3266T>C	p.Leu1089Pro	missense_variant	24/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2804T>C	p.Leu935Pro	missense_variant	22/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2411T>C	p.Leu804Pro	missense_variant	20/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spinocerebellar ataxia type 29 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Research Group Niklas Dahl, Uppsala University

Aug 01, 2016

We have identified a biallelic (homozygous) missense mutation in ITPR1 segregating with an autosomal recessive and early onset cerebellar syndrome. Heterozygous individuals are asymptomatic albeit with unequivocal cerebellar hypoplasia. Our findings add to the genetic complexity of Spinocerebellar ataxia (SCA) and broaden the correlations between ITPR1 variants and their clinical expression. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;.;.;.;.;.;M;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	D;D;.;D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.012	D;D;.;D;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;D;.;.;.;.;D;.;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.;.
Vest4		0.99
MutPred		0.71		.;.;.;.;.;.;Gain of catalytic residue at L1835 (P = 0.0317);.;.;.;.;
MVP		0.98
MPC		0.79
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1114167316; hg19: chr3-4776998;